TMPRSS6 Inhibition with a Monoclonal Antibody Improves Red Blood Cell Health and Reduces Hepatic Iron Loading in Mouse Models of Iron Overload Diseases

Beta-thalassemia is a genetic disorder arising from loss of function mutations in the beta-globin gene, leading to ineffective erythropoiesis and organ iron overload. The latter contributes to liver fibrosis, type-2 diabetes, cancer, and cardiac toxicities. The major cause of increased iron loading is the reduced hepcidin levels because of the ineffective erythropoiesis. Iron is regulated by the hormone hepcidin. The BMP6-HJV signaling axis induces hepcidin expression via SMAD1/5 activation and the serine-protease TMPRSS6 is a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene have high levels of circulating hepcidin resulting in iron-restricted/iron-deficiency anemia. Thus, blocking TMPRSS6 may be a viable strategy to elevate hepcidin and reduce iron levels in beta-thalassemia or hereditary hemochromatosis. We generated a monoclonal antibody (REGN7999) that inhibits TMPRSS6 activity hence preventing HJV cleavage. This in turn accentuates BMP6-HJV signaling, consequently increasing serum hepcidin. In the Hbbth3/+ mouse model of beta-thalassemia, treatment with REGN7999 (10 mg/kg, s.c., weekly for 8 weeks) led to a significant reduction in liver iron (~50% reduction compared to the isotype treated group) and improved red blood cell health as determined by Annexin V staining, intracellular oxidative stress, and measurement of red blood cell turnover. This effect on red blood cells was reflected by a longer running distance of Hbbth3/+ mice during forced exercise and a reduction in serum lactate production. Our data shows, that targeting TMPRSS6 has significant advantages over current treatments, such as Luspatercept, an ACVR2b receptor trap or iron chelation. These therapeutics target either red blood cell formation (Luspatercept) or iron loading (iron chelators), but not both. Hence, blockade of TMPRSS6 seems a good addition to current therapeutics. In addition, we tested REGN7999 in HFE-/-mice, a mouse model of hereditary hemochromatosis. After 8 weeks treatment, liver iron from HFE-/- mice was significantly reduced in these animals. Taken together, inhibition of TMPRSS6 is an advantageous strategy in different iron overload diseases.